Posttraumatic stress disorder (PTSD) is a chronic, debilitating, syndrome, with an estimated lifetime prevalence of approximately 7% in the United States. Although there are affective behavioral and pharmacological treatments for PTSD, substantial gaps in treatment remain. The generation of novel treatment options is therefore paramount. Reduced activation of the ventromedial prefrontal cortex (vmPFC) has consistently been observed in PTSD patients, and may represent a biological target for treatment. However, just how alterations in vmPFC function contribute to PTSD symptomology, or how this region might be pharmacologically targeted, is presently unknown. Although previous findings suggest that this brain region is likely to be important for the reduction of fear responses to stimuli whe they are no longer predictive of threat (fear extinction), recent evidence suggests that the vmPFC may also play a role in reducing the generalization of fear states to situations in which a threat has not been experienced (fear generalization). The studies in this proposal seek to advance our understanding of how hypofunction of the vmPFC contributes to PTSD risk and symptomology, and provide novel insight into how deficits in fear extinction and fear generalization in PTSD might be generated by distinct downstream output structures of the vmPFC. Using a rodent model of PTSD, the proposed experiments will first determine the time points at which vmPFC hypoactivity are likely to contribute to symptoms. This will be done by comparing the effects of inactivating the vmPFC at the time of trauma, at the time of fear generalization, or at the time of fear extinction. This will help to identify when interventions directed at the vmPFC are likely to be beneficial. Furthermore, this work will be the foundation for studies aimed at understanding what other brain regions the vmPFC works in concert with in the modulation of fear responses. Second, using novel technology that allows specific connections between the vmPFC and selected brain regions to be inactivated, it will be determined whether different vmPFC connections play distinct roles in fear extinction and fear generalization. In particular, the hypothesis to be tested is that projections from the vmPFC to the intercalated cells of the amygdala mediate fear extinction, whereas projections from the vmPFC to the bed nucleus of the stria terminalis mediate fear generalization. By elucidating the direct mechanism by which the vmPFC interacts with other brain regions in PTSD-related behaviors, potentially novel therapeutic targets can be discovered.